7. PROJECT SUMMARY/ABSTRACT Allergic airway inflammation, or asthma, occurs in approximately 8% of the US population. Although the pathogenesis and underlying cause driving the rising incidence of this chronic debilitating illness remains elusive, an important clue is consistently increased risk among children with early life antibiotic exposure. Similarly in animals, antibiotics that disrupt the composition of commensal intestinal bacteria exacerbate allergic airway inflammation. These protective properties of commensal bacteria in resiliency against asthma highlight the need for establishing how commensal bacteria confer these protective benefits. The classical reasoning for how antibiotics cause asthma susceptibility is that beneficial commensal bacteria that colonize the intestine and protect against allergic airway inflammation are inadvertently eliminated. However, given the efficiency whereby eradicating commensal bacteria inadvertently drives opportunistic overgrowth of Candida albicans and other immune modulatory fungi at mucosal interfaces, a more provocative explanation is that opportunistic fungal colonization positively calibrate and sensitize individuals to asthma. Accordingly, our overall hypothesis is that commensal bacteria protect against asthma by suppressing overgrowth by immune- modulatory fungi that sensitize individuals to allergic airway inflammation. This hypothesis is based on sharply increased severity of allergic airway inflammation triggered by fungal mold allergens among antibiotic treated animals colonized with intestinal fungi. Using recombinant C. albicans to establish intestinal colonization in antibiotic treated mice, our preliminary studies show skewed differentiation of peripheral CD4 T cells with fungal specificity into asthma promoting inflammatory T helper (Th)-17 and T follicular helper (Tfh) type 2 lineages. Accordingly, our specific aims are to (1) define the triggers of allergic airway inflammation and hyperreactivity sensitized by C. albicans intestinal colonization, (2) establish the durability whereby intestinal C. albicans colonization sensitizes to allergic airway inflammation, and (3) identify the early life developmental window when intestinal C. albicans colonization most efficiently imprints asthma susceptibility. This line of investigation has exciting potential to mechanistically explain why human early life exposure to antibiotics consistently increases asthma risk. The translational implications of our primary hypothesis that exposure to antibiotics indirectly cause asthma susceptibility, by fostering the opportunistic overgrowth of immune modulatory fungi, are that asthma susceptibility could be modified by simultaneously administering antifungal agents with antibiotics. In this scenario, establishing the developmental window and immunological basis for how opportunistic fungal colonization imprints asthma susceptibility is imperative. Accordingly, the aims of this exploratory grant seek to further investigate, refine and mechanistically develop this innovative hypothesis to unravel new insights on asthma disease pathogenesis essential for developing more effective therapies.